Summary The long-term goal of this research project is to understand the mechanism by which energy balance is regulated. Recent evidence has shown a critical role for brain-derived neurotrophic factor (BDNF) and its TrkB receptor in the control of energy balance. Mutations in the gene for BDNF or TrkB lead to obesity in both mice and humans that is more severe than melanocortin-4 receptor (MC4R) mutations and close to leptin deficiency. However, we know much less about the BDNF pathway than the melanocortin and leptin pathways with regard to the mechanisms underlying their roles in the control of energy balance. Therefore, elucidation of the mechanism by which the BDNF-TrkB pathway controls body weight will provide novel targets for development of obesity therapeutics. We have made tremendous progress in this research project during the prior award period. We have identified TrkB-expressing dorsomedial hypothalamus (DMHTrkB) and paraventricular hypothalamus (PVHTrkB) neurons as two appetite-regulating neuronal populations. We have found that deletion of the TrkB- encoding Ntrk2 gene in these neurons leads to hyperphagia and obesity and chemogenetic activation of these neurons dramatically suppresses food intake. Furthermore, our results indicate that DMHTrkB neurons also potently promote adaptive thermogenesis. This renewal application will test an overarching hypothesis that TrkB signaling controls energy balance by modulating synaptic function of neural circuits interconnecting with DMHTrkB and PVHTrkB neurons. More specifically, we will test this hypothesis in three specific aims. Aim 1 is to identify neural circuits through which DMHTrkB neurons regulate energy expenditure and appetite; Aim 2 is to Identify the targets and inputs of PVHTrkB neurons that control appetite; Aim 3 is to determine how BDNF-TrkB signaling regulates appetite by modulating synaptic function. This proposed research will uncover several novel neural circuits that regulate appetite and/or energy expenditure as well as novel mechanisms by which prandial state modulates the activity of appetite-controlling neural circuits through BDNF-TrkB signaling.